Therapeutic potential of mesenchymal stem cells for refractory inflammatory and immune skin diseases

ABSTRACT

Inflammatory and immunological skin diseases such as psoriasis, systemic sclerosis, dermatomyositis and atopic dermatitis, whose abnormal skin manifestations not only affected life quality but also caused social discrimination, have been wildly concerned. Complex variables such as hereditary predisposition, racial differences, age and gender can influence the prevalence and therapeutic options. The population of patients with unsatisfactory curative effects under current therapies is growing, it’s advisable to seek novel and advanced therapies that are less likely to cause systemic damage. Mesenchymal stem cells (MSCs) have been proven with therapeutic benefits in tissue regeneration, self-renewal and differentiation abilities when treating refractory skin disorders in preclinical and clinical studies. Here we highlighted the immune modulation and inflammation suppression of MSCs in skin diseases, summarized current studies, research progress and related clinical trials, hoping to strengthen the confidence of promising MSCs therapy in future clinical application.

KEYWORDS:

• MSC therapy
• psoriasis
• systemic sclerosis
• dermatomyositis
• atopic dermatitis

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Introduction

Skin is the largest organ of the body and the first physiological defense line against infection and maintains skin homeostasis and the skin consists of the epidermis, dermis and subcutaneous layer.¹ The epidermis is a layered flat epithelium with keratinocytes and tight junction, which form the first defense against outer invasions. Functional keratinocytes help to modulate the inflammatory and immune response through various methods like generating pro-inflammatory cytokines or promoting Th1 response when Toll-like receptors are activated.² Skin barrier dysfunction dissolves tight junctions of stratum granulosum that allow dendrites extension and antigens presentation.³ The dermis is a dense connective tissue with many elastic and collagen fibers, blood vessels, and nerves, which allows immune cells migration. Substances secreted by sweat and sebaceous glands also help skin defense.⁴

External stimuli like antigens or irritants and internal abnormalities like persistent skin inflammation increase the risk of skin barrier dysfunction. Skin diseases could be genetic and caused by other factors like environmental triggers, systemic diseases, and medications. The complex interplays make some skin diseases easy to relapse and difficult to cure. Psoriasis and atopic dermatitis (AD) are common chronic inflammatory skin diseases with substantial systemic burden and physical comorbidities. Due to their complex risk factors, multi-faceted evaluations before medical treatment are essential.^5,6 Systemic sclerosis and dermatomyositis are autoimmune connective tissue diseases with abnormal skin manifestations. Because the autoantigens are not tissue-specific, multiple organs disorders are also involved.⁷

A group of cells derived mainly from the third germ layer-mesoderm with the capability of differentiation and connective tissues building⁸ was recommended the name of multipotent mesenchymal stromal cells by the International Society for Cellular Therapy (ISCT) in 2006.⁹ Organs like bone marrow, umbilical cord, placental tissues, and adipose tissue are extensive sources of MSCs with different potentials of regulatory properties. Self-renewal, immunoregulation, anti-inflammatory, and low immunogenicity are the key properties of MSCs which make it possible in clinical management and avoiding allogeneic rejection.^10,11 Autologous or allogeneic MSCs have different advantages in medical practice.¹² However, different MSC type has its pros and cons. For example, though bone marrow stem cells are easy to isolate, the yield of them are relatively low and the differentiation capacity is limited. Human umbilical cord stem cells are primitive and strong in proliferation and differentiation but they can only be harvested from the donor once due to its origin.¹³ High yield and the capacity of maintain longer phenotype in culture make adipose-derived stem cells extensive for application, but the problem of limited differentiation capacity still exist.^14–16 So an ideal MSC type is also worth studying in specific clinical treatment.

MSCs could regulate primary and acquired immune responses by interacting with specific effector cells or secreting bioactive factors for their benefit. For example, studies have shown that contact between MSCs and serum could activate the complement system ^17,18 but the secretion of factor H which is a regulator of complement activation by MSCs themselves could rescue the effect.¹⁹ The extra addition of factor H to MSCs could also prevent complement-mediated damage.²⁰ These indicate autologous MSCs application and local modulation of the complement system may be ideal therapies to guarantee cellular viability and function. MSCs could increase phagocyte activity of neutrophils,²¹ regulate neutrophil phenotype,²² and balance tissue homeostasis by reduction of neutrophil oxidative burst via intercellular adhesion molecule 1 mediated engulfment of neutrophils.²³ TLR3 is overexpressed in human-induced pluripotent stem cells (iPSC), which serves as a negative regulator of the NF-KB p65 signaling pathway.²⁴ MSCs could sense combinations of multi-inflammatory cytokines like TNF-α, IL-1β and, IFN -γ and respond by modulating cytokine secretion and activating distinct pathways.²⁵ MSCs could induce metabolic shifts in differentially polarized macrophage and further promote macrophage differentiation,²⁶ as well as enhance M2 macrophage polarization.²⁷

MSC therapy has arisen interest in skin diseases due to its potential in immune modulation and anti-inflammatory capacity, which help skin lesions healing and re-epithelization by secreting various growth factors²⁸ and its safety and efficacy have been partially established.²⁹ Exosomes are secreted small bio-vesicles enriched with some cell-specific biological substances. MSC exosomes have shown the potential in diseases treatment with the properties of MSC.^30–32 For example, MSC exosomes could regulate mast cell activation under inflammatory conditions³³ and suppress mast cell activation by PGE2 production and EP4 activation.³⁴ What’s more, during MSC culture, there are plenty of proteins and lipid mediators secreted in the MSC-conditioned medium and could be preserved without losing efficacy. Such cell-free products have been used for treating skin diseases.^35,36

MSC therapy in psoriasis

Psoriasis is a common immune-mediated chronic inflammatory skin disease that causes erythematous, itchy scaly patches with a high incidence, a long course of the disease, and a tendency to relapse. The imbalance between the Th1/Th17 and chemokines and cytokines like IL-17, IL-23, TNFα, and IFN-γ promote psoriasis pathogenesis which could be briefly explained as dysfunction of keratinocytes, immune and inflammatory cells.³⁷ Some cases are almost incurable for life, which may lead to adult comorbidities like psoriatic arthritis and atherosclerotic cardiovascular disease.³⁸ Targeted phototherapy and prescribing biologics targeting key immune pathways in the psoriasis pathogenesis like infliximab (TNF-α),³⁹ ustekinumab (IL-12/23),⁴⁰ secukinumab (IL-17)⁴¹ and guselkumab (IL-23),⁴² significantly improve the life quality of patients with moderate to severe psoriasis.⁴³ However, not all patients respond to biological drugs and may experience adverse effects without any clinical improvement.⁴⁴

Preclinical studies about MSC infusion in psoriasis models were carried out for several years (Figure 1). For example, subcutaneous application of extracellular superoxide dismutase transduced MSCs has been proven to prevent disease development in mice,⁴⁵ and MSC alone could inhibit proinflammatory cytokines or chemokines like IL6, IL7, TNF-α, CCL17, CCL20, and CCL27.⁴⁶ A recent study has proved that MSCs could reduce the production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) and rebalance the Th1, Th2, and Th17 responses.⁴⁷ Topical application of MSC exosomes could also alleviate psoriasis-associated inflammation by inhibiting complement activation.⁴⁸

Figure 1. MSC therapy could rebalance the amount and function of immune cells and suppress inflammatory mediators in psoriasis model.

A male patient who had received various psoriasis treatments for 25 years without ideal efficacy showed significant improvement after intravenous transplantation (3.0 × 10⁶ cells/mL) and local transplantation (1.0 × 10⁶ cells/mL) of umbilical cord-derived MSCs transplantation.⁴⁹ And in the long follow-up of 4 to 5 years, a female patient showed no psoriatic relapse signs after three infusions and two more consolidating infusions of umbilical cord-derived MSCs (1.0 × 10⁶/kg for each time). Unexpected psoriasis relief was observed in a male patient who had suffered psoriasis for 12 years during the treatment of newly diagnosed diffuse large B-cell lymphoma (stage IV) with standard lymphoma chemotherapies and autologous hematopoietic stem cell transplantations.⁵⁰

Several clinical trials also show confidence in the potential of MSC application in psoriasis treatment from a clinical perspective (Table 1). Both intravenous and subcutaneous injections were adopted as delivery routes. The dose of (0.5–3.0) *10⁶ cells/kg was commonly used by intravenous injection, while the dose of (0.1–2.0) *10⁸ cells was adopted in subcutaneous injection. At least 12 weeks of follow-up is necessary for efficacy assessment of intravenous injection and 4 weeks for subcutaneous injection. MSC exosome has been made as a kind of ointment for topical treatment and the follow-up of 20 days. PASI (Psoriasis Area and Severity Index) score is the most common criterion as a primary outcome in different trials.

Table 1. Clinical trials of MSC therapy in psoriasis.

ClinicalTrials.gov Identifier	Locations	Phase	Estimated Enrollment	Age	Route of delivery	Dose	Frequency	Follow up	Type of MSC	Primary outcome	Secondary outcome
NCT03765957	Xiangya Hospital, Central South University, China	Early Phase 1	12 participants	18–65 years (Adult, Older Adult)	Intravenous infusion.	(1.5–2) *10^6 cells/kg or (2.5–3) *10^6 cells/kg	4 times (week 0,2,4,6)	6 months	Human Umbilical Cord-derived Mesenchymal Stem Cells	PASI75 and PGA at month6	DLQI and AE at baseline and month6
NCT03745417	Guangdong Provincial Hospital of Traditional Chinese Medicine, China	Phase 1, 2	5 participants	18–65 years (Adult, Older Adult)	Intravenous infusion.	2 × 10^6 cells/kg	5 times (week 0,2,4,6,8).	12 weeks	Human Umbilical Cord-derivedMesenchymal Stem Cells	PASI score at 12 weeks (plus or minus 3 days)	PASI score, relapse rate, Pruritus scores, BSA%, DLQI at 12 weeks (plus or minus 3 days)
NCT04785027	Guangdong Provincial Hospital of Traditional Chinese Medicine, China	Phase 1, 2	16 participants	18–65 years (Adult, Older Adult)	Intravenous infusion.	2 × 10^6 cells/kg	5 times (week 0,2,4,6,8).	12 weeks	Allogeneic Adipose-derived Mesenchymal Stem Cells	PASI score at 12 weeks (plus or minus 3 days)	PASI score, relapse rate, Pruritus scores, BSA%, DLQI at 12 weeks (plus or minus 3 days)
NCT03392311	Guangdong Provincial Hospital of Traditional Chinese Medicine, China	Phase 1, 2	8 participants	18–65 years (Adult, Older Adult)	Intravenous infusion	2 × 10^6 cells/kg	5 times (week 0,2,4,6,8).	12 weeks	Adipose-derived multipotent mesenchymal stem cells	PASI score at 12 weeks (plus or minus 3 days)	PASI score, relapse rate, Pruritus scores, BSA%, DLQI at 12 weeks (plus or minus 3 days)
NCT04275024	Guangdong Provincial Hospital of Traditional Chinese Medicine, China	NotApplicable	8 participants	18–65 years (Adult, Older Adult)	Intravenous infusion	2 × 10^6 cells/kg	5 times (week 0,2,4,6,8).	12 weeks	Adiposederived multipotent mesenchymal stem cells	PASI score at 12 weeks (plus or minus 3 days)	PASI score, relapse rate, Pruritus scores, BSA%, DLQI at 12 weeks (plus or minus 3 days)
NCT03265613	Guangdong Provincial Hospital of Traditional Chinese Medicine, China	Phase 1, 2	7 participants	18–65 years (Adult, Older Adult)	Intravenous infusion.	0.5 × 10^6 cells/kg	3 times (week 0,4,8).	12 weeks	Adipose-derived multipotent mesenchymal stem cells	AE, SAE at 12 weeks (plus or minus 3 days)	PASI score, Pruritus scores, BSA%, DLQI at 12 weeks (plus or minus 3 days)
NCT02491658	Affiliated Hospital to Academy of Military Medical Sciences, China	Phase 1, 2	30 participants	18–65 years (Adult, Older Adult)	Unclear	1.0 × 10^6 cells/kg	6 times (week 0,1,2,3,5,7)	1 year	Human Umbilical Cord-derived Mesenchymal Stem Cells	PASI score and DLQI at baseline and 8 weeks	Body temperature, blood pressure up to 3 months. PASI score and DLQI at month 6,9,12
NCT03424629	Peking University Third Hospital and Tianjin Ever Union Biotechnology Co., Ltd., China	Phase 1	57 participants	18–60 years (Adult)	Intravenous infusion.	1.0 or 3.0 × 10^6 cells/kg	6 times (week 0,1,2,3,5,7)	52 weeks	Human Umbilical Cord-derived Mesenchymal Stem Cells	PASI75 and PGA at week 6	PASI90 at week20.PASI75 and PGA at week 12,16,36,52.AE and SAEs form week 0 to 52. Relapse from week 8 to 52.
NCT02918123	The Catholic Univ. Korea Seoul, St. Marry’s Hospital, Korea	Phase 1	9 participants	19–65 years (Adult, Older Adult)	Subcutaneous injection	0.1 or 0.5 or 2.0 × 10^8 cells	Once	4 weeks	Human Umbilical Cord-derived Mesenchymal Stem Cells	AE, safety lab tests, physical examination, ECG, vital signs, variation of Cytokine, PASI, BSA at 4 weeks follow up	Not applicable
NCT05523011	National University Hospital, Singapore	Phase 1	10 participants	21 years and older (Adult, Older Adult)	Topical	100 µg	Three doses per day, 20 days	20 days	MSC Exosome ointment	TEAEs, Vital signs and blood test, Visual assessments of the area of application based on SCORAD	Not applicable

PASI 75, Psoriasis Area and Severity Index ≥75%.

PGA, Physician Global Assessment.

DLQI, Dermatology Life Quality Index.

AE, Adverse event.

SAE, Serious adverse event.

ECG, Electrocardiograph.

BSA%, the Body Surface Area.

SCORAD, SCORing Atopic Dermatitis.

TEAEs, Treatment-emergent adverse events.

MSC therapy in systemic sclerosis

Systemic sclerosis (SSc) is a rare multisystem disease that causes progressive fibrosis of the skin and visceral organs, characterized by localized or diffuse skin thickening and fibrosis, microvascular dysfunction, and immune system abnormally activation.⁵¹ The chronic course of disease and complications of multiple organ dysfunction significantly reduce the life span and life quality of patients.⁵² Briefly, the disease starts with the activation of autoimmune response, leading to damage of endothelial and subsequent production of autoantibody and cytokines. Macrophages, immune cells including T and B lymphocytes, and dendritic cells are the main functionally abnormal cells in skin lesions.^53,54 Excessive fibrosis produced by myofibroblasts further aggravates organ and blood vessel damage. Based on the pathogenesis, therapies like immunosuppression, antifibrotic agents, and immunomodulators have been applied to relieve pain or improve organ function⁵⁵ and the therapeutic effect of intravenous immunoglobulins has also been proved.⁵⁶ However, it’s still a challenge to comprehensive assessment for individual-based treatment precisely because of the multiple organ complications in SSc. A safer therapy without many side effects will bring hope to SSc patients.

Promotion of angiogenesis,⁵⁷ secretion of substances in vascular repair⁵⁸ and anti-fibrosis effects^59–61 make stem cells great therapeutic potentials in SSc. The advantages of adipose stem cells (ADSCs) in low immunogenicity and easy acquirement⁶² achieve its role in SSc treatment.^63,64 In the bleomycin-induced fibrosis mice model, intravenous application of ADSCs prevents lung and skin fibrosis, and accelerates wound healing.⁶⁵ In clinical applications, autologous fat grafting could correct and improve facial beauty by recreating fullness⁶⁶ and injection of autologous adipose-derived stromal vascular fraction in fingers significantly improves hand disability.⁶⁷ Though these findings were enlightening, the capacity of adipocytic progenitors of differentiation into myofibroblasts might aggravate fibrosis⁶⁸ and exposure to MSCs in SSc may increase their myofibroblast differentiating potential.⁶⁹

A female SSc patient who developed acute gangrene of the upper and lower limbs recovered revascularization after three infusions of autologous mesenchymal stem cells.⁷⁰ And study has found that allogeneic MSCs retain their therapeutic effects under the oxidative environment of SSc.⁷¹

Most of the current clinical studies deliver autologous or allogeneic MSCs by intravenous infusion. And various MSC types from adult umbilical cord, Wharton’s jelly, adipose tissue and bone marrow are adopted. At least 12 weeks for skin score evaluation and adverse events monitoring is needed. The most reported common dose of MSCs was 1.0 × 10⁶ cells (Table 2).

Table 2. Clinical trials of MSC therapy in systemic sclerosis.

ClinicalTrials.gov Identifier	Location	Phase	Estimated Enrollment	Age	Route of delivery	Dose	Frequency	Follow up	Type of MSC	Primary outcome	Secondary outcome
NCT05016804	Medical Surgical Associates Center,	Phase 1	20 participants	Child, Adult, Older Adult	Intravenous Infusion	1.0 × 10^6 cells	once	4 years	Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cell	adverse events	skin score and FVC
NCT00962923	the Affiliated Drum Tower Hospital of Nanjing University Medical School, China	Phase 1, 2	20 participants	15–65 years (Child, Adult, Older Adult)	Intravenous infusion	1.0 × 10^6cells/kg	Once	Unclear	Allogeneic mesenchymal stem cells	mRSS score, HRQOL score, SF-36 score	Remission for organ function, DLCO, PAP, blood test, SSc Serology, Change of peripheral blood B and T cells
NCT04432545	Universidad de la Sabana， Colombia	Not applicable	Not applicable	18–65 years (Adult, Older Adult)	Intravenous infusion	2.0 × 10^6 cells/kg	ten days after each application of thecyclophosphamide schedule	6 months	Allogeneic mesenchymal stem cells from Wharton ́s jelly	Unclear	Unclear
NCT02213705	Saint-Louis Hospital, France	Phase 1, 2	20 participants	18–70 years (Adult, Older Adult)	Unclear	Unclear	Unclear	2 years	allogeneic mesenchymal stem cells	Toxicity (2 years)	Survival, progression free survival, Rodnan score (2 years), Clinical response (3, 6, 9, 12 months)
NCT02975960	Seoul St. Mary’s hospital, Korea	Not Applicable	7 participants	18 years and older (Adult, Older Adult)	Unclear	Unclear	Unclear	12 weeks	Adipose Tissue-derived Mesenchymal Stem Cells	mRSS of hands	Raynaud’s condition score, Visual Analog Score, Kapandji score, Cochin hand function scale, Systemic sclerosis HAQ, peripheral vasculature, finger circumference
NCT03211793	Universitair Medisch Centrum Utrecht, Netherlands	Phase 1, 2	20 participants	18 years and older (Adult, Older Adult)	Intramuscular injection	5.0 × 10^7 cells	8 intramuscular injections at designated sites	52 weeks	Allogeneic bone marrow derived mesenchymal stem cells	Toxicity of thetreatment	SAE, Numerical Rating Scale, digital ulcer visual analogue scale, perceived pain based on the use of analgesics, SF-36, HAQ-DI, Hand function, EQ-5D-5 L .,etc
NCT01745783	University Hospital Reina Sofia, University Regional Hospital Carlos Haya, University Hospital Virgen Macarena, Spain	Phase 1, 2	26 participants	18–50 years (Adult)	Intravenous infusion	1-2 × 10^6 cells/kg	once	12 months	Autologous bone marrow derived mesenchymal stem cells	SAE	Disease activity on magnetic resonance, EDSS, MSFC, life quality, outbreaks, disease-free patients

mRSS, modified Rodnan Skin Score.

FVC, Forced Vital Capacity.

HSCT, Hematopoietic Stem Cell Transplant.

SAEs, serious adverse reactions.

HRQOL, health-related quality of life.

SF-36, Short-Form 36.

DLCO, diffusion capacity for carbon monoxide.

EDSS, Expanded Disability Status Scale.

MSFC, Changes Multiple Sclerosis Functional Composite.

PAP, pulmonary artery pressure.

HAQ-DI, Health Assessment Questionnaire-Disability Index.

EQ-5D-5 L, EuroQol-5-Domain-5-Level health questionnaire.

MSC therapy in dermatomyositis

Dermatomyositis is a rare, multi-system, autoimmune, and inflammatory myopathy characterized by typical heliotrope rash, Gottron’s sign and papules, splinter hemorrhage of the nail fold, and symmetric, proximal muscle weakness.⁷² Patients can present single or several cutaneous manifestations and there is no clinical parallelism between cutaneous and muscle manifestations. Perivascular infiltration of CD4+ lymphocytes can be found in skin biopsies.⁷³ Though there is no exact reason, potential pathogenic factors like MHC polymorphisms,⁷⁴ environmental factors, and abnormal activation of the immune system are all threatening for susceptible individuals. Myositis-specific antibodies like anti-Mi2, anti-MDA5, and anti-TIF1 are associated with the diagnosis and prognosis of DM.⁷⁵ Existent therapies are symptom management. For example, intravenous immunoglobulin, and corticosteroids alone or combined with immunosuppressive agents like azathioprine and methotrexate, or intravenous immunoglobulins are the main therapies⁷⁶ to improve the condition. But clinical relapses and non-responders are still the headaches.

Early between May 2008 and July 2009, 10 patients with drug-resistant polymyositis or dermatomyositis received allogeneic mesenchymal stem cell transplantation with the dose of 1.0 × 10⁶ cells/kg of body weight by intravenous infusion. Ideal clinical responses were demonstrated but whether a single MSC application could be the replacement was not sure because none of the patients stopped immunosuppressive therapy in the follow-up.⁷⁷ Recently, a long-time follow-up study of three patients with the diagnosis of refractory juvenile dermatomyositis showed complete remission after autologous hematopoietic stem cell transplantation.⁷⁸ A case reported a patient whose cutaneous symptoms and morphology of bone marrow aspirate were significantly improved after allogeneic hematopoietic stem cell transplantation.⁷⁹

There are currently two clinical trials based on human umbilical cord-derived MSC therapy for dermatomyositis by intravenous infusion (Table 3). The Dose Limiting Toxicity is the main primary outcome in the follow-up. But the ideal dosage and frequency need more clinical clues.

Table 3. Clinical trials of MSC therapy in dermatomyositis.

ClinicalTrials.gov Identifier	Location	Phase	Estimated Enrollment	Age	Route of delivery	Dose	Frequency	Follow up	Type of MSC	Primary outcome	Secondary outcome
NCT04723303	University of Florida, USA	Early Phase 1	22participants	18–90 years (Adult, Older Adult)	Intravenous infusion	0.5 or 1.0 or 2.0 × 10^8 cells	Unclear	Unclear	Umbilical Cord Lining Stem Cells	DLT(within24 hours)	Not applicable
NCT04976140	Seoul National University College of Medicine, Soonchunhyang University Seoul Hospital, Hanyang University Seoul Hospital, Korea	Phase 1， 2	18 participants	19 years and older (Adult, Older Adult)	Intravenous infusion	Unclear	Unclear	12 weeks	Human umbilical cord mesenchymal stem cell (UC-MSC) derived allogeneic mitochondria	DLT, IMACS-TIS	IMACS-TIS, response rate of IMACS-TIS, CSAM, CDASI and PPNRS

DLT: Dose Limiting Toxicity.

PBSC: peripheral blood stem cell.

IMACS-TIS: international Myositis And Clinical Studies group-Total Improvement Score.

CSAM: Core Set Activity Measures.

CDASI: Cutaneous Dermatomyositis Disease Area and Severity Index.

PPNRS: Peak Pruritus Numeral Rating Scale.

MSC therapy in atopic dermatitis

Atopic dermatitis (AD) is an intractable, chronic and relapsing skin disease with unpleasant pruritus. Approximately 20% of children and 10% of adults are affected by AD in high-income countries. Complex causes like epidermal barrier dysfunction and allergen exposure result in innate and adaptive immune disorders and abnormal inflammatory response.⁸⁰ Because AD is easy to relapse and difficult to cure, the major aims of disease management are symptom improvement and long-term control. Topical treatments are effective in mild atopic dermatitis patients while phototherapy, topical steroids and systemic immunosuppressant drugs are most commonly used in moderated to severe patients. Concerns exist like skin thickness decrease by overusing corticosteroid cream or ointment, side effects on the immune system by calcineurin inhibitors, and the increased risk of skin cancer by long-term light therapy. Biological agents like IL­4 Rα antagonists Dupilumab,^81,82 IL­13 inhibitor tralokinumab,⁸³ JAK1 inhibitor upadacitinib⁸⁴ and abrocitinib,⁸⁵ JAK1 and JAK2 inhibitor baricitinib,⁸⁶ have shown good therapy potential in moderate-to-severe atopic dermatitis, but full course is still a heavy financial burden to patients and their families.

The therapeutic effects of MSC have been demonstrated by several studies (Figure 2). For example, MSC infusion could suppress mast cell degranulation by increasing PGE2 and TGF-β1,⁸⁷ rebalance Th1, Th17, and Th2,⁸⁸ and decrease cytokines or chemokines like IL-1β, IL4, IL5, IL6, IL13, IL17, CCL5, TNF-α, IFN-γ, TSLP and IgE.^89–91 Even MSC-derived exosomes, conditioned medium and extracts were found to relieve atopic dermatitis.^36,92,93 Researchers also found either preconditioned with mast cell granules, poly I: C, or IFN-γ could improve MSC therapeutic effects.^94,95 Both intravenous and subcutaneous MSC infusion were effective in mouse models.^8,91,94

Figure 2. The anti-inflammatory effect and immune modulation of MSC or its cell-free products in atopic dermatitis model.

In current clinical trials, injection of human umbilical cord-derived stem cells intravenously is the most common therapy with the dosage varies from 2.5 × 10⁷ to 3.0 × 10⁸ cells. 31 patients with moderate-to-severe AD have completed a clinical trial in which they received MSCs subcutaneously with a low dose of 2.5 × 10⁷ cells and a high dose of 5.0 × 10⁷ cells, respectively. The therapeutic effects of AD manifestation presented a dose-dependent manner.⁹⁶ Other 5 patients without ideal respondence to conventional treatments were administrated with 1.0 × 10⁶ cells/kg MSCs intravenously and showed good clinical improvement in the follow-up.⁹⁷ Various studies with a larger number of patients, more reasonable grouping and MSC dose selection criteria are working together for clinical efficacy demonstration (Table 4).

Table 4. Clinical trials of MSC therapy in atopic dermatitis.

ClinicalTrials.gov Identifier	Location	Phase	Estimated Enrollment	Age	Route of delivery	Dose	Frequency	Follow up	Type of MSC	Primary outcome	Secondary outcome
NCT02888704	Chungnam National University Hospital，Korea	Phase 1	13participants	19–70 years (Adult, Older Adult)	Intravenous infusion	1.0 or3.0 × 10^8 cells	Once	12 weeks	Adult humanmesenchymal stem cells	AE (12 weeks follow-up after treatment)	SCORAD, IGA, EASI, Serum IgE, PGE2, ECP, CCL17, CCL27
NCT03252340	Chungnam National University Hospital，Korea	Phase 1	11 participants	19–70 years (Adult, Older Adult)	Intravenous infusion	1.0 or 3.0 × 10^8 cells	Once	60 months	Adult human mesenchymal stem cells	Tumor formation (60 months)	AEs (60 months)
NCT01927705	Catholic Medical Center, Korea	Phase 1, 2	34participants	20–60 years Adult	Unclear	2.5or5.0 × 10^7 cells	once	4 weeks	Human Umbilical Cord Blood derived-Universal Stem Cells	SCORAD Index (4 weeks follow-up after treatment)	SCORAD total score and index, the degree of disease, IGA, EASI, Serum IgE (4 weeks follow-up after treatment)
NCT03458624	Seoul ST. Mary’s Hospital, Korea	Phase 1	14 participants	19–70 years (Adult, Older Adult)	Intravenous infusion	Unclear	Unclear	3 years	Unclear	AE (3 years)	SCORAD, IGA, EASI, Serum IgE (3 years)
NCT05004324	Chosun University Hospital, Korea	Phase 3	308 participants	19 years and older (Adult, Older Adult)	Unclear	5.0 × 10^7 cells/1.5 ml	Once with five regions (both upper arms, both thighs, and abdomen)	12 weeks	Human Umbilical Cord Blood derived-Universal Stem Cells	EASI	EASI, IGA, SCORAD, BSA, NRS, POEM, DLQI, Resuce medicine (week 2,4,8,12,24)
NCT03269773	Pusan National University Hospital, Chonnam National University Hospital, Dongguk University Medical Center, Gachon University Gil Medical Center, Catholic Medical Center, Asan Medical Center, Chung-Ang University Healthcare System, Hanyang University Medical Center, Samsung Medical Center, Seoul National University Hospital, Ajou University Hospital	Phase 3	197 participants	19 years and older (Adult, Older Adult)	Unclear	5.0 × 10^7 cells/1.5 ml		24 weeks	Human Umbilical Cord Blood derived-Universal Stem Cells	EASI50	EASI, IGA, SCORAD, BSA, IgE, TNF-a, IL-4, IL-5, IL-6, IL-8, IL-13, IL-31, TARC (CCL17) and CCL 27, Total number of use and consumed amount of rescue medicine (week12,24)
NCT04179760	Inha University Hospital, Korea	Phase 1, 2	92 participants	19 years and older (Adult, Older Adult)	Intravenous infusion	1.0 × 10^6 cells/kg	3 times (week 0,2,4)	24 weeks	Allogeneic human bone marrow-derived mesenchymal stem cells	EASI50	EASI, IGA, NRS, BSA, SCORAD, DLQI, POEM, IgE, eosinophil count, IL13, IL17, TRAC, IL22 (week 4, 8, 12, 16, 20, 24)
NCT04137562	Chungnam National University Hospital, Korea University AnSan Hospital, Chung-Ang University Hospital, Kyunghee University Medical Center, Seoul National University Hospital, SMG-SNU Boramae Medical Center	Phase 2	118 participants	19–70 years (Adult, Older Adult)	Intravenous infusion	0.5 × 10^8 cells/5 mL	Twice	5 years	Adult human mesenchymal stem cells	EASI50 (week16)	EASI, SCORAD, Severity, IGA, IGEPGE2, ECP, immune cytokine, Remedy used days, frequency and subjects (week 4,8,12,16).

SCORAD, SCORing Atopic Dermatitis.

IGA, Investigator’s global assessment.

EASI, eczema area and severity index.

AE, Adverse event.

IgE, Immunoglobulin E.

PGE2, prostaglandin E2.

ECP, eosinophil cationic protein.

CCL17, Chemokine ligand 17.

CCL27, Chemokine ligand 27.

NRS, Numerical Rating Scale.

POEM, Patient-Oriented Eczema Measure.

DLQI, Dermatology Life Quality Index.

BSA, Body Surface Area.

Discussion

Long-term and sustained treatments for chronic and refractory skin diseases can cause unwilling side effects and maybe a heavy economic stress. MSCs are promising in tissue repairing, immune and inflammatory modulation. Though there are effective biological agents available for skin diseases like psoriasis and atopic dermatitis, many MSC therapy related clinical trials are ongoing. with the expect for more effective and safe alternatives with persistent curative effects. For diseases which is not common but severe like systemic sclerosis and dermatomyositis and systemic diseases, MSC therapy will be benefit more from these properties.

Though the safety and efficacy of MSCs in clinical application have been confirmed by emerging studies, administration route, standard dose, injection speed and frequency still need more evidence in applying under certain circumstances. It’s also worth considering under individual-based treatment that multidisciplinary judgment is a must when in combination with other diseases. A deep understanding of profound mechanisms of MSC therapy may in turn help find novel therapeutic targets for a certain disease.

Authors’ contributions

CH collected references, summarized clinical trials and wrote the manuscript. SC drew the graphical summaries. HC reviewed and checked the article. The authors have approved the final manuscript.

Acknowledgments

This study was supported by grants from the Key science and technology R&D project of Zhejiang Province (2021C03077).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The work was supported by the the Key science and technology R&D project of Zhejiang Province [2021C03077].